Directors from the extremely labor intensive task of creating chronic animals and caring for their immediate post operative recovery. The Core will also provide echocardiographic assessment on animals prior to and during the development of heart failure or sham fime controls. The Animal Models Core has worked very effectively over the past 10 years of this PPG. Various animal models will be prepared by or under the supen/ision of Dr. Kurtis G. Cornish who has had many years of experience in the preparafion of chronic animals and is experienced in these specific animal preparations. He will be assisted by three technicians in the preparation and care of animals prior to their use by the PPG invesfigators. The models prepared by this Core will be (1) the coronary ligafion model of heart failure (HF) in the rat, and (2) the pacing model of HF in the rabbit. Assessment of the cardiac status of all animals is obtained echocardiographically. The Core is supported by two echocardiographs. Rabbit imaging is done on an Accuson Sequoia 5120 machine and rodent images are obtained on a Visual Sonics Vevo 770. Ms. Johnnie Hackley is primarily responsible for obtaining the data on the rats and rabbits prior to, during and after the inducfion of heart failure. A. Surgical Preparation of Animal Models 1. Rat model of heart failure: coronary ligation. Sprague-Dawley rats (200+ g, males) will be assigned randomly to one of two groups, HF or sham animals. The heart failure animals will have their left coronary artery ligated near its bifurcafion from the aorta. Sham rats will undergo the same surgery but the coronary arteries will not be tied, consistent with the procedure used by us and by other laboratories^'^. The rat will be anesthefized with 2% Isoflurane and given 6 pg atropine/100 gm body weight im. An endotracheal tube will be inserted orally in order to administer positive pressure ventilation. A thoracotomy will be done at the 4^ intercostal space on the left side. Once intubated, the chest will be shaved and scrubbed with surgical soap and then painted with Betadine. All surgeries in this Core will be done following strict sterile procedures. In the HF group, the left coronary artery will be ligated with 6-0 Proline suture, just below its exit from the aorta, between the pulmonary artery outflow tract and left atrium. Prior to the ligafion, 0.5 mg of lidocaine will be injected SQ to help prevent potenfially lethal arrhythmias. Adequate coronary occlusion will be evidenced by cardiac enlargement and blanching of the myocardium. A chest tube will then be inserted in the 6'*^ intercostal space and exited 0.5 cm below this point. Following these maneuvers the thorax will be closed and evacuated. As the rats begin to breathe spontaneously, the fluid and air in the chest will be evacuated and the chest tube removed. Control rats will undergo thoracotomy and the manipulafion of the heart, treated with lidocaine, but the coronary ligature will not be placed. After the animal begins to show signs of recovery, the endotracheal tube will be removed and the rats will be allowed to recover from the anesthesia. The rats will then be placed in individual cages until the day of the experiment. The rats will be housed in a room with a 12-hour light-dark cycle, an ambient temperature maintained at 22C and humidity of 30-40%. Laboratory chow (Purina) and tap water will be available acf libitum. In our hands there is an inifial (immediately or 24 hour) mortality rate of 21% for the infarcted rats. After completion of surgery the rats will be treated prophylactically with analgesics: 1. approximately 45 minutes before recovery from the anesthetic the rats will be given Buprinorphine at a dose of 0.05 mg/kg; 2. Then they will receive Buprinorphine 0.05 mg/kg SQ every 12 hours. This will be done for the first 2 post-operative days. Rats will be delivered to the PI at the time prescribed by the experimental protocol. 234